During the past century, land use change, such as settlement development and intensification of agriculture, has led to a decreased capacity of natural floodplains to provide flood regulation across large areas of Europe. The expansion of built-up areas in flood zones has reduced retention areas, potentially leading to an increase of downstream flood risk and an increased demand for flood regulation measures. The goal of this paper was to analyse the historic development of settlements from the 1850s until 2011 in relation to flood exposure in the upper reaches of the river Main, Germany. The settlement area of pre-industrial times was derived from historical land cover maps with the aid of object-based classification. Current settlement areas were extracted from the real estate map of Bavaria. Topographic and flood exposure variables were utilized for the statistical analysis of settlement change. Results showed a strong increase in settlements in all administrative districts of the case study area since the 1850s. The total built-up area within the flooding zone of the investigated section of the Main river increased almost fivefold. Such expansion of settlement into the natural floodplains indicates a high growth in demand for flood regulation. Furthermore, our results suggest that flood exposure affected site selection of settlement in the past much stronger than it does today. Technical flood control (e.g. channels, dams and retention areas) reduced the area of settlement at risk for many towns in the case study region, but for some, it remains remarkably high.